The present invention provides a novel method and apparatus for non-invasive regional brain thermal stimulation for treating neurological disorders. In particular, the present invention has novel applications for neuropsychiatric disorders in which there are alterations in whole brain metabolism. Such disorders, include, by way of example but not limitation, insomnia, anxiety disorders, including obsessive compulsive disorder (OCD), sleep apnea syndrome and depression. More broadly, however, the present invention is effective in any neurological disorder in which an alteration in metabolism in a localized area may be beneficial.
One such brain disorder that illustrates the benefits of the present invention is insomnia. A recent NIH State-of-the-Science Conference “Manifestations and Management of Chronic Insomnia in Adults”, noted that “insomnia is the most common sleep complaint across all stages of adulthood, and for millions of people, the problem is chronic.” Many health and lifestyle factors can contribute to insomnia including stress, depression, medical illnesses, pain, medications, or specific sleeping disorders. The panel concluded that “there is great need for additional research to better define the nature of chronic insomnia.” While recognizing evidence from both psychological and physiological models in the etiology of insomnia, the conference encouraged more research by concluding that “the neural mechanisms underlying chronic insomnia are poorly understood . . . ” and that “ . . . studies aiming to identify neural mechanisms should use animal models and in vivo neural imaging approaches in people with insomnia and in individuals with normal sleep.”
Existing treatments of neurological and/or sleeping disorders, including insomnia, include the use of over the counter or prescription drugs and/or behavioral treatments. Prescription drugs are known to aid patients suffering from sleeping disorders, however, these drugs can be quite expensive and potentially addicting. Some medications even become less effective as use continues. Additionally, the prescriptions can have unwanted and harmful side effects.
Other techniques to treat sleeping disorders include a variety of behavioral measures including stimulus control therapy, sleep restriction therapy, relaxation training, cognitive therapy, and sleep hygiene education. While these measures have moderate effectiveness, they are costly, require significant time to implement and require highly trained clinicians to implement.
The present invention addresses these issues and those relating to other neurological disorders through using a novel method and apparatus for non-invasive and localized or regional thermal stimuli to the brain that helps treat neurological or neuropsychiatric disorders. In the case of sleeping disorders or depression, again as an example but not as a limitation on the full scope of the present invention, the restoration of function in the cerebral cortex plays a significant role in sleep. At the molecular and neuronal levels, hypothesized functions of sleep include the restoration of brain energy metabolism through the replenishment of brain glycogen stores that are depleted during wakefulness and the downscaling of synapses that have been potentiated during waking brain function. A homeostatic sleep drive, or pressure for sleep, is known to build throughout the waking hours and then is discharged during sleep. At the electroencephalographic (EEG) level, this is measured by EEG spectral power in the delta (0.5-4 Hz) frequency band.
These sleep-related processes have some regional specificity for the prefrontal cortex. Slow wave sleep rhythms have both thalamic and cortical components. An anterior dominance of EEG spectral power in the delta EEG spectral power range has been reported. A frontal predominance for the increase in delta power following sleep loss has been also reported. This region of the cortex also plays a prominent role in waking executive functions which are preferentially impaired following sleep deprivation. These sleep deprivation induced cognitive impairments have been related to declines in frontal metabolism after sleep loss. While cerebral metabolism declines globally from waking to NREM sleep, these declines are most pronounced in heteromodal association cortex, including the prefrontal cortex.
Insomnia is associated with global cerebral hypermetabolism. Nofzinger et al. (Am J Psychiatry, 2004) assessed regional cerebral glucose metabolism during both waking and NREM sleep in insomnia patients and healthy subjects using [18F] fluoro-2-deoxy-D-glucose positron emission tomography (PET). Insomnia patients show increased global cerebral glucose metabolism during sleep and wakefulness; and a smaller decline in relative metabolism from wakefulness to sleep in wake-promoting regions of the brain. In a comparison between insomnia and depressed patients, insomnia patients demonstrated increased waking relative metabolism in the prefrontal cortex. Finally, recent research has shown that the amount of wakefulness after sleep onset, or WASO, in insomnia patients correlates with increasing metabolism in the prefrontal cortex during NREM sleep.
The relationship between body temperature and quality of sleep generally have been described in connection with prior research in the field of sleep medicine. Heat loss, via selective vasodilatation of distal skin regions (measured by the distal minus proximal skin temperature gradient (DPG), seems to be a crucial process for the circadian regulation of core body temperature (CBT) and sleepiness (Aschoff 1956; Krauchi and Wirz-Justice 1994, 2002; Krauchi et al. 1998, 2000). Increased DPG before lights off has been noted to promote a rapid onset of sleep, suggesting a link between thermoregulatory and arousal (sleepiness) systems (Krauchi et al. 1999, 2000). Hot environments impair the sleep process including falling asleep and maintaining sleep as well as generating slow wave sleep as the increased ambient temperature interferes with the normal declines in core body temperature associated with the sleep onset process. Finally, rapid and intense temperature drops around the sleep onset or sleeping periods are expected to have an arousing effect (Horne and Reyner 1999; Hayashi et al. 2003). In contrast, the present invention minimizes such adverse effects from temperature changes through application of a less intense hypothermic stimulus over a prolonged period of time to a localized surface of the scalp. More specifically, the present invention utilizes the application of a noninvasive, regional thermal stimulus, either through warming or cooling, to the scalp of the head to adjust metabolism in the cerebral cortex underlying the stimulus and, thereby, provide treatment for neurological disorders.
Existing technologies for brain cooling involve either whole body cooling or whole brain cooling. Most commonly employed is whole body cooling. Less commonly applied is whole brain cooling, which includes some invasive techniques. Of the below-listed devices, none have been used for the treatment of neuropsychiatric disorders such as depression or anxiety disorders, or neurological disorders such as sleeping disorders including insomnia.
For example, regulation of overall body temperature in an attempt to aid patients in falling asleep is disclosed in U.S. Pat. No. 5,441,476 to Kitado et al. Prior to the present invention, however, generalized temperature regulation has not proven efficacious in the field of sleep medicine. Adverse effects of entire body cooling include: (i) infections; (ii) coagulopathy; (iii) cardiac arrhythmias; (iv) arterial hypotension; and (v) shivering (leading to anesthesia).
Also known in the art, is the cooling of a particular organ for surgical purposes as demonstrated in U.S. Pat. No. 6,979,345 B2 to Werneth. In this reference, a device performs hypothermia to a patient or a particular organ of a patient, while administering a medication to a blood vessel. Additionally, U.S. Pat. Nos. 5,957,963, 6,149,667, 6,231,595 B1 and 6,818,011 B2 all to Dobak, III, disclose a method and apparatus for performing hypothermia of an entire selected organ without significant effect on surrounding organs or other tissues. The cooling protects the tissue from injury caused by anoxia or trauma. An advantage of these inventions is that they reduce the need for whole body cooling, but they do not address the noninvasive, regionalized thermal stimulation method of the present invention.
Brain cooling devices are also available which reduce the risk of secondary brain injury after initial brain injury to a patient. For example, see U.S. Pat. No. 6,929,656 B1 to Lennox, which teaches an apparatus and method for reducing secondary brain injury. Unlike the present invention, though, this apparatus includes an invasive brain cooling probe and a control console. The brain cooling probe cools the brain to prevent secondary injury by cooling the cerebrospinal fluid within one or more brain ventricles.
Further, U.S. Pat. No. 6,986,783 B2 to Gunn et al. teaches a method for preventing or reducing the development of delayed brain damage in a patient, comprising the steps of applying generalized cooling headwear to the patient's head, thermostatically controlling the coolant temperature within a predetermined range to maintain the brain at a temperature below normal for an extended period of time sufficient to prevent the death of neurons, glial or other cells that would otherwise die as a consequence of direct injury to the brain or other injury to the patient likely to cause injury to the brain. Unlike the present invention, this method is designed to produce whole brain cooling using temperature changes that, in the case of treatment for sleep disorders, are too severe to allow sleep to occur or be maintained. The present invention differs from this prior art in that it uses the localized or regional application of a hypothermic stimulus that, in one embodiment, is in a range that can be used for the induction and maintenance of sleep.
The related art also teaches cooling blood flowing to the brain. For example, U.S. Pat. No. 6,682,552 B2 to Ramsden et al. discloses a device and system for use in a pre-hospital setting to cool the brain after an injury. The cooling effect of this invention is specifically geared towards cooling the blood flowing through the carotid artery to the brain. Likewise, U.S. Pat. No. 5,916,242 to Schwartz discloses a neck encircling apparatus for brain cooling in firm contact with the soft tissue of the neck, and particularly in thermal contact with the carotid arteries traversing the neck. Distinct from the present invention, neither of these devices allows for regional or localized brain cooling at temperature ranges that may permit sleep and its beneficial results for treatment of certain brain disorders.
Devices for brain cooling of an infant are also known, as shown in U.S. Pat. No. 6,312,453 B1 to Stefanile et al. This device is used where the infant has suffered hypoxic shock.
U.S. Pat. No. 5,261,399 to Klatz et al. teaches a brain cooling device and method for brain cooling. The device is a helmet for positioning on the head of the patient. The cooling is intended to prevent ischemic and anomic injuries whereby the patient survives neurologically intact. Another example is demonstrated in U.S. Pat. No. 7,008,445 B2 to Lennox, which teaches a cooling helmet. In both of these disclosures, generalized cooling of the brain occurs by a helmet that encompasses the entirety of a head region, while the present invention, again, focuses on localized or regional cooling or warming of the brain.
Similarly, U.S. Pat. No. 6,126,680 to Wass which discloses a method and apparatus for generalized convective cooling of a brain in which cooled air is passed over the entirety of a patient's head resulting in convective cooling of the patient's brain.
More generally, while direct application of a thermal stimulus to the cerebral cortex is not feasible in human clinical trials, general research on brain cooling has shown that the application of a cooling stimulus to the scalp decreases brain temperature in the underlying cortex in both animals and humans. For example, in a study of pigs, even a mild surface cooling of 15 degrees Celsius was associated with cooling of the scalp and superficial brain to 35 degrees Celsius. Iwata et al Pediatric Int. 2003. In this study, there was a notable differential effect of surface cooling on superficial vs. deep brain tissue, with superficial brain tissue cooled to a greater degree than deep brain tissue. The change in underlying brain temperature was achieved in 30-75 minutes. In a human study, (Wang et al. 2004) researchers were able to decrease surface brain temperatures by an average of 1.84 degrees Celsius within 1 hour of subjects wearing a whole head cooling helmet. Systemic hypothermia (<36 degrees Celsius) did not occur until 6.67 hours after application of the cooling stimulus. Biomedical engineering models (Diao et al. 2003) also suggest that rapid cooling (within 26 minutes) of the brain gray matter can be achieved by selective head cooling on the surface. While the purpose of this research focused on techniques for generalized brain cooling, the present invention specifically utilizes non-invasive and regionalized thermal stimulation, including brain cooling for the purposes of reducing brain metabolism in a specific brain region and not others, and thereby provides treatment for neurological disorders.
Prior to the present invention, generalized brain cooling has been known only to protect the brain against damage caused by loss of blood flow or loss of oxygen to brain tissue in several clinical circumstances such as head trauma, stroke and protection against neuronal insult during cardiopulmonary surgery. Preclinical studies have shown neuroprotective beneficial effects of brain cooling in several domains. These include: metabolism (1970); pH (1992); neurotransmitter levels (1982); free fatty acids (1989); blood-brain barrier (1990); edema (1987); glucose metabolism (1987); cerebral blood flow (1954); free radical activation (1994); lipid peroxidation (1994); calcium accumulation (1992); protein synthesis (1991); protein kinase-C activity (1991); leukocyte accumulation (1991); platelet function (1987); NMDA neurotoxicity (1991); growth factors (1994); cytoskeletal proteins (1993); calcium-dependent protein phosphorylation (1990); warm shock protein (1992); immediate early genes (1996); NOS activity (1999); and MMP expression (2003).
Further, the benefit of mild (30 degrees Celsius-34 degrees Celsius) hypothermia in global and focal ischemia has been recognized. Therapeutic hypothermia to improve neurological outcome after global and focal ischemic events affecting the brain has also shown beneficial results in controlled animal and human studies. However, no practical device for or method of treatment of neurological disorders has resulted from these studies.
The present invention provides a method of noninvasive, regional brain thermal stimulation to aid in the treatment of neurological or neuropsychiatric disorders that has not been utilized in the prior art. In fact, nothing in the related art patents discloses or suggests any teaching regarding the treatment of neurological disorders, such as sleeping disorders, via brain cooling or warming. The related art further does not provide an apparatus for regional brain thermal adjustment to treat neurological disorders, such as sleeping disorders or depression.